Poster Title

Disrupting the Circadian Clock Mechanism in Cardiomyocytes Exacerbates the LQT3-related phenotype in Scn5a(ΔKPQ/+) Mice

Grade Level at Time of Presentation

Senior

Major

Biology

Minor

Spanish

Institution

University of Kentucky

KY House District #

75

KY Senate District #

13

Department

Department of Physiology

Abstract

Introduction: The pro-arrhythmic LQTS type 3 (LQT3) is caused by gain-of-function mutations in the cardiac Na+ channel Scn5a. LQT3 patients typically have an abnormally long heart rate-corrected QT-interval (QTc), but even patients with the same disease-causing mutation show a wide range of clinical phenotypes. This suggests additional factors influence the LQT3-related phenotype.

Hypothesis: Many LQT3 patients show an increased incidence in life-threatening arrhythmias at night. We tested the hypothesis that disruption of the cardiomyocyte molecular clock that underlies circadian rhythms modifies the LQT3-related phenotype.

Methods: We used in vivo ECG telemetry of control mice and mice that harbor an LQT3-causing mutation (Scn5aΔKPQ/+). All animals were genetically engineered to enable us to induce the deletion of Bmal1, a key component of the molecular clock, in adult cardiomyocytes. We calculated the RR-interval, QT-interval, and the QTc-interval using the correction formula from Mitchell et al. AJP 1998.

Results: Before Bmal1 deletion, Scn5aΔKPQ/+ mice showed a prolongation in the RR, QT and QTc-intervals compared to control animals. Bmal1 deletion slowed the RR and QT-intervals in both groups, but the QTc-interval remained unchanged. Linear regression analysis revealed that the slope of the QT-RR relation in Scn5aΔKPQ/+ mice was double that of control animals and Bmal1 deletion increased the slope in both groups. Additionally, Bmal1 deletion lengthened the QT-interval at a lower RR-interval in Scn5aΔKPQ/+ animals compared to control.

Conclusion: Inducing Bmal1 deletion in control and Scn5aΔKPQ/+ mice did not change the QTc interval, but increased the slope of the QT-RR relation so at slower RR-intervals there is a greater change in the QT-interval. Scn5aΔKPQ/+ mice showed the greatest QT prolongation at slow RR-intervals. We conclude that disruption in the molecular clock mechanism exacerbates the LQT3-related phenotype, especially at slow heart rates.

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Disrupting the Circadian Clock Mechanism in Cardiomyocytes Exacerbates the LQT3-related phenotype in Scn5a(ΔKPQ/+) Mice

Introduction: The pro-arrhythmic LQTS type 3 (LQT3) is caused by gain-of-function mutations in the cardiac Na+ channel Scn5a. LQT3 patients typically have an abnormally long heart rate-corrected QT-interval (QTc), but even patients with the same disease-causing mutation show a wide range of clinical phenotypes. This suggests additional factors influence the LQT3-related phenotype.

Hypothesis: Many LQT3 patients show an increased incidence in life-threatening arrhythmias at night. We tested the hypothesis that disruption of the cardiomyocyte molecular clock that underlies circadian rhythms modifies the LQT3-related phenotype.

Methods: We used in vivo ECG telemetry of control mice and mice that harbor an LQT3-causing mutation (Scn5aΔKPQ/+). All animals were genetically engineered to enable us to induce the deletion of Bmal1, a key component of the molecular clock, in adult cardiomyocytes. We calculated the RR-interval, QT-interval, and the QTc-interval using the correction formula from Mitchell et al. AJP 1998.

Results: Before Bmal1 deletion, Scn5aΔKPQ/+ mice showed a prolongation in the RR, QT and QTc-intervals compared to control animals. Bmal1 deletion slowed the RR and QT-intervals in both groups, but the QTc-interval remained unchanged. Linear regression analysis revealed that the slope of the QT-RR relation in Scn5aΔKPQ/+ mice was double that of control animals and Bmal1 deletion increased the slope in both groups. Additionally, Bmal1 deletion lengthened the QT-interval at a lower RR-interval in Scn5aΔKPQ/+ animals compared to control.

Conclusion: Inducing Bmal1 deletion in control and Scn5aΔKPQ/+ mice did not change the QTc interval, but increased the slope of the QT-RR relation so at slower RR-intervals there is a greater change in the QT-interval. Scn5aΔKPQ/+ mice showed the greatest QT prolongation at slow RR-intervals. We conclude that disruption in the molecular clock mechanism exacerbates the LQT3-related phenotype, especially at slow heart rates.